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WO2024260929A1 - Agonistes de trem2 - Google Patents

Agonistes de trem2 Download PDF

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Publication number
WO2024260929A1
WO2024260929A1 PCT/EP2024/066833 EP2024066833W WO2024260929A1 WO 2024260929 A1 WO2024260929 A1 WO 2024260929A1 EP 2024066833 W EP2024066833 W EP 2024066833W WO 2024260929 A1 WO2024260929 A1 WO 2024260929A1
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Prior art keywords
dimethyl
chloro
phenyl
tetrahydropyran
fluoro
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Pending
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PCT/EP2024/066833
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English (en)
Inventor
Stefan Berchtold
Virginie BROM
Julie CHARPENTIER
Maria Emilia Di Francesco
Guido Galley
Luca Claudio Gobbi
Wolfgang Guba
Roland Johann HUMM
Marie-Paule IMHOFF
Fionn Susannah O'HARA
Angélique PATINY-ADAM
Flore Marie Aude REGGIANI
Nicolas ZEIDAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Publication of WO2024260929A1 publication Critical patent/WO2024260929A1/fr
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Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R.C. et al., Science 2011, 9;333(6048):1456-8 doi: 10.1126/science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L.F. et al., Mol.
  • Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs.
  • Ig-SF Immunoglobulin superfamily
  • Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem.2015;290(25):15866–77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities.
  • Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and A ⁇ oligomers. Stimulation of the TREM2/DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP12, which results in recruitment of Syk kinase to activate downstream signaling molecules.
  • ITAM immunoreceptor tyrosine-based activation motif
  • TREM2 Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C.
  • TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J. et al., Am J Hum Genet. 2002,71(3):656-62, doi: 10.1086/342259).
  • NBD Nasu-Hakola Disease
  • PLOSL Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy
  • TREM2 missense mutations of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • PD Parkinson’s disease
  • ALS amyotrophic lateral sclerosis
  • FTD frontotemporal dementia
  • GWAS genomic-wide association studies
  • the present invention provides compounds of formula (I) wherein A 1 , A 2 , X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , and R 7 are as defined herein.
  • the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).
  • Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith.
  • alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms.
  • the alkoxy group contains 1 to 3 carbon atoms.
  • alkyl examples include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C 1-6 -alkoxy”).
  • the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms.
  • Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non- limiting example of alkoxy is methoxy.
  • halogen or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • halogen refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).
  • cycloalkyl refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C 3-10 -cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl.
  • Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl.
  • aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-C10-aryl”), wherein at least one ring in the system is aromatic.
  • Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl).
  • a particularly preferred, yet non-limiting example of aryl is phenyl.
  • heteroaryl refers to a mono- or multivalent, monocyclic ring system having a total of 5 to 6 ring members, wherein the ring system is aromatic and contains one or more heteroatoms.
  • the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, the heteroaryl comprises 1 to 2 heteroatoms independently selected from O, S and N.
  • Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g.2- pyridyl); pyrazolyl (e.g.
  • heteroaryl refers to a saturated or partly unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon.
  • heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, and thietanyl.
  • Preferred, yet non-limiting examples of heterocyclyl groups include 1,2-dihydropyridiynl and oxetanyl.
  • haloalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro.
  • haloalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro.
  • Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl.
  • alkoxyalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, preferably methoxy.
  • alkoxyalkyl refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, most preferably methoxy.
  • alkoxyalkyl is 2-methoxyethyl.
  • cycloalkylalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, preferably cyclopropyl.
  • cycloalkylalkyl refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, most preferably cyclopropyl.
  • a particularly preferred, yet non-limiting example of cycloalkylalkyl is cyclopropylmethyl.
  • cycloalkylalkoxy refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, preferably cyclopropyl.
  • cycloalkylalkoxy refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, most preferably cyclopropyl.
  • a particularly preferred, yet non-limiting example of cycloalkylalkoxy is cyclopropylmethoxy.
  • the term “cycloalkyoxy” refers to a cycloalkyl group as defined herein, wherein the cycloalkyl group is bound to the parent molecule trough an oxygen atom.
  • a particularly preferred, yet non- limiting example of cycloalkyoxy is cyclobutyloxy.
  • heterocyclylalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, preferably oxetanyl.
  • heterocyclylalkyl refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, most preferably oxetanyl.
  • a particularly preferred, yet non-limiting example of heterocyclylalkyl is oxetanylmethyl.
  • heterocyclylalkoxy refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, preferably oxetanyl.
  • heterocyclylalkoxy refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, most preferably oxetanyl.
  • a particularly preferred, yet non-limiting example of heterocyclylalkoxy is oxetanylmethoxy.
  • heterocyclyloxy refers to a heterocyclyl group as defined herein, wherein the heterocyclyl group is bound to the parent molecule trough an oxygen atom.
  • a particularly preferred, yet non-limiting example of heterocyclyloxy is oxetanyloxy.
  • pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.
  • treatment includes: (1) inhibiting the state, disorder or condition (e.g.
  • prophylaxis as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A 1 , X 1 and X 2 are each independently selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is selected from C 6 -C 10 -aryl, 5- to 6-membered heteroaryl and C 3 -C 10 -cycloalkyl, wherein said C6-C10-aryl, 5- to 6-membered heteroaryl and C3-C10-cycloalkyl are optionally substituted with 1-3 substituents independently selected from halogen, C1- C6-alkyl and halo-C1-C6-alkyl; R 3 is selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl and 3-
  • the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 1 , X 1 and X 2 are each independently selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is selected from C6-C10-aryl and C3-C10-cycloalkyl, wherein said C6-C10-aryl and C3- C 10 -cycloalkyl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R 3 is selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein said 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from hal
  • the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is a compound of Formula (Ia) wherein: A 1 , X 1 and X 2 are each independently selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is selected from C 6 -C 10 -aryl and C 3 -C 10 -cycloalkyl, wherein said C 6 -C 10 -aryl and C 3 - C 10 -cycloalkyl are optionally substituted with 1-3 substituents independently selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R 3 is a 5- to 6-membered heteroaryl that is optionally substituted with 1-3 substituents independently selected from C 1 -C 6 -alky
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 is CH and X 2 is N; or (ii) X 1 is N and X 2 is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH and X 2 is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is CH. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are both CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 2 is selected from O and CR 5 R 6 ; R 5 and R 6 are both hydrogen or R 5 and R 6 are both halogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 2 is selected from O and CR 5 R 6 ; R 5 and R 6 are both hydrogen or R 5 and R 6 are both fluoro. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A 2 is O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 2 is CR 5 R 6 ; R 5 and R 6 are both hydrogen or R 5 and R 6 are both fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (II) or (III): wherein the variables are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (II): wherein the variables are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (III): wherein the variables are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl and CHF2.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 6 -C 10 -aryl, C3-C10-cycloalkyl, and 5- to 6-membered heteroaryl comprising 1-2 heteroatoms independently selected from N, O and S, wherein said C6-C10-aryl, C3-C10-cycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen and halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, wherein said phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are optionally substituted with 1-3 substituents independently selected from fluoro, chloro, CHF 2 , and CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C6- C10-aryl and C3-C10-cycloalkyl, wherein said C6-C10-aryl and C3-C10-cycloalkyl are substituted with 1-3 substituents independently selected from halogen and halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane substituted with 1-3 substituents independently selected from fluoro, chloro, and CHF2.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from: F F
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein said phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted with 1-3 substituents independently selected from fluoro, chloro, CHF 2 , and CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with 1-3 halogen substituents.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with 1-3 substituents selected from fluoro and chloro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from 5- to 6- membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, where
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein said pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with 1-2 substituents independently selected from methyl, ethyl, isopropyl, CHF 2 , CF 3 , 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from C1-C6- alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, and 3- to 6-membered heterocyclyl, and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and optionally one further substituent selected from C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10-cycloalkyl.
  • R 3 is selected from 5- to 6-membered heteroaryl comprising
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein said pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with 1 substituent selected from methyl, methoxy, cyclopropyl, and oxetanyl, and wherein said 1,2-dihydropyridine is substituted with oxo and optionally one further substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl.
  • R 3 is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydr
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: N N O O N N N F F F
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2-dihydropyridine, wherein said pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with 1-2 substituents independently selected from methyl, CF3, methoxy, cyclopropyl, and oxetanyl, and wherein said 1,2-dihydropyridine is optionally substituted with 1-2 substituents independently selected from methyl, CF3, methoxy, cyclopropyl, and oxetanyl, and
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen and methyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen and methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is selected from C6-C10-aryl, C3-C10-cycloalkyl, and 5- to 6-membered heteroaryl comprising 1-2 heteroatoms independently selected from N, O and S, wherein said C6-C10-aryl, C3-C10-cycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogen and halo-C1- C 6 -alkyl; R 3 is
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is selected from methyl and CHF 2 ; R 2 is selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, wherein said phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are optionally substituted with 1-3 substituents independently selected from fluoro, chloro, CHF2, and CF3; R 3 is selected from pyridyl, pyrazolyl, 1,3,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 is CH and X 2 is N; or (ii) X 1 is N and X 2 is CH; A 1 is CH; A 2 is O; R 1 is selected from C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl; R 2 is selected from C 6 -C 10 -aryl and C 3 -C 10 -cycloalkyl, wherein said C 6 -C 10 -aryl and C 3 - C10-cycloalkyl are substituted with 1-3 substituents independently selected from halogen and halo-C 1 -C 6 -alkyl; R 3 is selected from 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 is CH and X 2 is N; or (ii) X 1 is N and X 2 is CH; A 1 is CH; A 2 is O; R 1 is selected from methyl and CHF 2 ; R 2 is selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane substituted with 1-3 substituents independently selected from fluoro, chloro, and CHF2; R 3 is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2- dihydropyridine, wherein said pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4- oxadiazolyl are substituted with 1 substituent selected from methyl, methoxy, cyclopropyl,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is C1-C6-alkyl; R 2 is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein said phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted with 1-3 substituents independently selected from fluoro, chloro, CHF2, and CF3; R 3 is selected from pyridyl pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2- dihydropyridine, wherein said
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is C 1 -C 6 -alkyl; R 2 is phenyl substituted with 1-3 halogen substituents; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl; R 4 is selected from hydrogen and methyl; R 5 and R 6 are both hydrogen or R 5 and R 6 are both halogen; and R 7 is C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 1 , X 1 and X 2 are all CH; A 2 is O; R 1 is methyl; R 2 is phenyl substituted with 1-3 substituents selected from fluoro and chloro; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl; R 4 is hydrogen; and R 7 is methyl.
  • a 1 , X 1 and X 2 are all CH; A 2 is O; R 1 is methyl; R 2 is phenyl substituted with 1-3 substituents selected from fluoro and chloro; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cycloprop
  • the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is C1-C6-alkyl; R 2 is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein said phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted with 1-3 substituents independently selected from fluoro, chloro, CHF2, and CF3; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and
  • the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 2 are both CH; or (ii) X 1 is CH and X 2 is N; or (iii) X 1 is N and X 2 is CH; A 1 is selected from N and CH; A 2 is selected from O and CR 5 R 6 ; R 1 is C 1 -C 6 -alkyl; R 2 is phenyl substituted with 1-3 halogen substituents; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl; R 4 is selected from hydrogen and methyl; and R 5 and R 6 are both hydrogen or R 5 and R 6 are both halogen.
  • the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A 1 , X 1 and X 2 are all CH; A 2 is O; R 1 is methyl; R 2 is phenyl substituted with 1-3 substituents selected from fluoro and chloro; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl; and R 4 is hydrogen.
  • a 1 , X 1 and X 2 are all CH; A 2 is O; R 1 is methyl; R 2 is phenyl substituted with 1-3 substituents selected from fluoro and chloro; R 3 is selected from pyridyl and pyrazolyl, wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from methyl, methoxy, and cyclopropyl; and R
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-(4-
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-(4-
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydro
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxan-4-yl]- 2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3- (difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazol- 4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.
  • the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein.
  • the present invention provides compounds according to formula (I) as described herein as free bases or acids.
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
  • isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Certain isotopically-labeled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • Substitution with heavier isotopes, such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes.
  • Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.
  • compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization.
  • Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds.
  • the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.
  • This intermediate can be reacted with amine V in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N- methylpyrrolidone to form Ia (nucleophilic substitution).
  • a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N- methylpyrrolidone to form Ia (nucleophilic substitution).
  • compound IV can be reacted with amine V using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(0), a suitable ligand such as Xantphos and a base such as cesium carbonate or sodium tert.-butoxide to form compound Ia (metal-catalysed coupling).
  • a palladium source such as tris(dibenzylideneacetone) dipalladium(0)
  • a suitable ligand such as Xantphos
  • a base such as cesium carbonate or sodium tert.-butoxide
  • intermediate IV can either be directly reacted with an organozinc reagent VI using palladium-catalysed conditions, or first with boronic acid derivative VII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound Ib.
  • Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine.
  • This intermediate can then react with ketoester X in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form compound IV.
  • Scheme 4 compounds of general formula Ib can be prepared as described in Scheme 4 by reacting intermediate IV first with bis(pinacolato)diboron under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound XII.
  • a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene
  • a base such as cesium carbonate or sodium carbonate
  • intermediate IV can be reacted with bororic ester derivative XVIII under palladium catalysed conditions (a palladium source such as (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)- palladium(0) and a base such as cesium carbonate or sodium carbonate) to form as well compound XVII.
  • this intermediate is reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound XIX.
  • the ester functionality can then be transformed into various heterocyclic residues R 3 by multi-step reactions known to people skilled in the art and published in various literature reviews such as J. Chem.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.
  • TREM2 Agonistic Activity Compounds of the present invention are TREM2 agonists.
  • the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject.
  • TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12.
  • the resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.
  • frozen HEK293-TREM2/DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 ⁇ L of DMEM media without Phenolred and supplemented with 5% FBS.
  • Compounds in dose response (1:3) were diluted in DMSO (highest concentration 10mM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 ⁇ l cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells).
  • DMSO Neutral
  • stimulator (1 ⁇ M tool compound) controls were also added. Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5 ⁇ L of lysis buffer was added by using the Certus. After a quick spin, plates were shaken for 30 minutes at 450 RPM, at room temperature and in the dark. After complete lysis, AlphaLisa reagents were added by Certus to the lysate, and fluorescence intensity was measured using a Pherastar plate reader (Excitation: 680nm/Emission: 615nm). EC50 values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound.
  • TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in table 1.
  • TREM2 agonistic potencies of reference compounds as measured in the assay described above are presented in table 2.
  • Table 1 hTREM2 hTREM2 Ex. Ex. EC 50 ( ⁇ M) EC 50 ( ⁇ M) 1 0.327 4 0.086 2 1.01 5 1.27 3 0.078 6 0.729 hTREM2 hTREM2 Ex. Ex.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.
  • the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.
  • said condition associated with a loss of function of human TREM2 is Parkinson’s disease.
  • said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.
  • said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.
  • said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the upper limit given herein can be exceeded when this is shown to be indicated. Examples
  • the invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.
  • the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers.
  • the asymmetric carbon atom can be of the "R" or "S" configuration.
  • Step 2 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3-amine 100 mg, 0.388 mmol
  • ethyl 2-methylacetoacetate 559 mg, 564 ⁇ l, 3.87 mmol
  • bismuth trichloride (12 mg, 0.038 ⁇ mol, 0.10 eq
  • the mixture was degassed, filled with argon, and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (50 mg, 0.06 mmol, 0.1 eq) was added. After stirring at 60 °C for 18 h, the mixture was evaporated in vacuo. The residue was diluted with water (100 ml) and extracted with ethyl actate (2 x 100 ml), then the combined organic layers were filtered through anhydrous sodium sulfate and evaporated in vacuo.
  • Step 2 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one 5-Chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine (170 mg, 0.616 mmol), ethyl 2- methylacetoacetate (888 mg, 897 ⁇ l, 6.16 mmol) and polyphosphoric acids (85 mg) were mixed at room temperature and the mixture was stirred for 6 h at 120 °C. The reaction mixture was diluted with water and extracted three times with ethyl acetate.
  • Step 2 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • 6-chloro-4-(4-chloro-2,6-difluoro-phenyl)pyridazin-3-amine 210 mg, 0.76 mmol
  • ethyl 2-methylacetoacetate 1.1 g, 1.11 ml, 7.61 mmol
  • bismuth trichloride 24 mg, 0.076 mmol, 0.10 eq
  • Step 2 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrazino[1,2- a]pyrimidin-4-one
  • 4,4-difluoro-3-keto-2-methyl-butyric acid ethyl ester (CAS 425394-84-9, 3.49 g, 19.4 mmol)
  • polyphosphoric acid 250 mg
  • 5-chloro-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-amine 500 mg, 1.94 mmol
  • reaction mixture was degassed while bubbling argon through it.
  • a freshly prepared solution of ammonium persulfate (2.36 g, 10.3 mmol) in purged dimethylsulfoxide / water (600/1) was added under argon and the mixture was stirred at 40 °C for 20 h.
  • the reaction mixture was quenched with a saturated solution of NaHCO 3 and extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step 2 7-bromo-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2- a]pyrimidin-4-one
  • 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazin-2-amine (170 mg, 0.55 mmol) and ethyl 2-methylacetoacetate (796 mg, 805 ⁇ l, 5.52 mmol) was added bismuth trichloride (17 mg, 0.055 mmol, 0.10 eq) at room temperature and the mixture was stirred at 100 °C for 18 h.
  • reaction mixture was heated to 80 °C and stirred for 20 h. After cooling to room temperature the reaction mixture was filtered over Celite and washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidin-4-one (1.8 g, 85% yield) as orange oil.
  • reaction mixture was degassed while bubbling nitrogen through it.
  • a freshly prepared solution of ammonium persulfate (6.34 g, 27.79 mmol) in purged dimethylsulfoxide / water (600/1) was added under nitrogen and the mixture was stirred at 40 °C for 20 h.
  • the reaction mixture was quenched with a saturated solution of NaHCO3 , the pH was adjusted to 8-9 and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness.
  • Step 2 7-chloro-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-pyrimido[1,2- b]pyridazin-4-one
  • 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyridazin-3-amine 190 mg, 0.77 mmol
  • ethyl 2-methylacetoacetate 556 mg, 3.87 mmol
  • p-toluene sulfonic acid 27 mg, 0.15 mmol
  • Step 2 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine
  • [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate 870 mg, 2.31 mmol
  • 1,4-dioxane 15 ml
  • bis(pinacolato)diboron (1.17 g, 4.62 mmol)
  • potassium acetate 906 mg, 9.23 mmol
  • 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex 189 mg, 0.231 mmol, 0.10 eq).
  • the mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h.
  • the reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated.
  • Step 2 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethanone
  • 2-chloro-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethanone (25.0 g, 109.32 mmol) in dimethylsulfoxide (250 ml) was added potassium carbonate (30.2 g, 219 mmol), potassium iodide (18.15 g, 109.3 mmol) and 1-(benzylamino)propan-2-ol (CAS 27159- 32-6, 18.06 g, 109.32 mmol) and the mixture was stirred at 20 °C for 2 h.
  • reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (300 ml x 3), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 ⁇ m, 100 ⁇ ; mobile phase: water + 0.1% formic acid / acetonitrile 10-15%, flow rate 200 ml/min).
  • Step 3 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]propan-2-ol
  • 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4- yl)ethanone (26.0 g, 72.7 mmol) in methanol (260 ml) was added sodium borohydride (8.26 g, 218 mmol, multiple times in batches) at 0 °C, and the mixture was stirred at 0 °C for 1 h.
  • Step 4 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine
  • 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4- yl)ethyl]amino]propan-2-ol (24.0 g, 66.8 mmol) in 1,4-dioxane (96 ml) at 20 °C was slowly added water (48 ml) and hydrochloric acid (37% in water, 48 ml, 576 mmol).
  • reaction mixture was stirred at 110 °C for 2 h, then cooled to room temperature and the pH was adjusted to 8 by aqueous saturated NaHCO3 solution.
  • the aqueous layer 1000 ml was extracted with dichloromethane (300 ml x 3). The combined organic layers were washed with brine (500 ml x 3), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 5 4-benzyl-2-methyl-6-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine
  • a solution of 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine (1.0 mg, 3.89 mmol) in dimethylformamide (20 ml) was added cesium carbonate (3.17 g, 9.71 mmol) and 3-iodooxetane (1.07 g, 5.83 mmol) and the mixture was stirred at 50 °C for 16 h.
  • the reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3).
  • Step 6 2-methyl-6-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine
  • methanol 20 ml
  • palladium on charcoal 10%, 340 mg
  • the reaction was stirred at 50 °C for 12 h under hydrogen atmosphere (15 Psi), then cooled to room temperature and filtered through a pad of Celite.
  • reaction mixture was cooled down to 0 °C, trifluoromethane sulfonic acid (4.84 g, 2.86 ml, 32.26 mmol) was added in portions and the mixture was stirred 30 min at 0 °C and then 4 h at room temperature.
  • the reaction mixture was poured into saturated NaHCO 3 solution and extracted two times with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in heptane) to afford the title compound (1.2 g, 23% yield) as colorless liquid.
  • trifluoromethane sulfonic acid 55.2 ml, 624 mmol was added in portions at -10 °C and the mixture was stirred at -10 °C for 2 h.
  • the reaction mixture was poured into aqueous NaHCO3 solution (400 ml) and extracted with dichloromethane (200 ml x 3). The combined layers were washed with brine (200 ml), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 [6-[1-(oxetan-3-yl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate
  • a solution of [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (4.0 g, 13.41 mmol) in dimethylformamide (32 ml) was added 3-iodooxetane (12.3 g, 67.1 mmol) and cesium carbonate (8.74 g, 26.8 mmol) and the reaction mixture was stirred at 50 °C for 16 h.
  • Step 2 trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran- 6-yl]pyrazol-1-yl]methoxy]ethyl]silane
  • [6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate 2.1 g, 4.9 mmol) in 1,4-dioxane (20 ml) was added bis(pinacolato)diboron (1.49 g, 5.88 mmol), potassium acetate (1.44 g, 14.7 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (200 mg, 0.25 mmol, 0.05
  • Step 2 trimethyl-[2-[(4-morpholin-2-ylpyrazol-1-yl)methoxy]ethyl]silane
  • 2-[[4-(4-benzylmorpholin-2-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane 820 mg, 2.2 mmol
  • methanol 5 ml
  • palladium on charcoal 10%, 233 mg
  • reaction was degassed in vacuo and hydrogen was added (3 times). The mixture was stirred at 50 °C for 12 h under a hydrogen atmosphere of 45 Psi.
  • Step 2 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole
  • diethyl (bromodifluoromethyl)phosphonate CAS 65094-22-6, 1.73 g, 1.15 ml, 6.49 mmol
  • acetonitrile 40 ml
  • potassium fluoride 754 mg, 13 mmol
  • 4-(4- bromotetrahydropyran-2-yl)-1H-pyrazole 1.0 g, 4.33 mmol
  • Step 2 2-(1-cyclobutylpyrazol-4-yl)morpholine
  • methanol 5 ml
  • palladium on charcoal 10%, 143 mg
  • the reaction was degassed with hydrogen 3 times and stirred at a hydrogen atmosphere of 45 Psi at 50 °C for 12 h.
  • the reaction mixture was cooled down to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound (260 mg, 93% yield) as colorless oil.
  • Step 2 [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate
  • acetonitrile 20 ml
  • bromomethylcyclopropane 934 mg, 671 ⁇ l, 6.92 mmol
  • potassium carbonate 1.27 g, 9.22 mmol
  • Step 2 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridin-2-one
  • methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate (1 g, 4.11 mmol) in toluene (30 ml) was added diisobutylaluminum hydride solution (1.2 M in toluene (10.28 ml, 12.34 mmol) dropwise under argon at -78 °C and the mixture was stirred at -78 °C for 3 h. Then diethylether was added and the mixture was allowed to warm to 0 °C.
  • Step 3 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carbaldehyde
  • 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridin-2-one 880 mg, 4.09 mmol
  • dichloromethane 25 ml
  • manganese dioxide 3.56 g, 40.9 mmol
  • the reaction mixture was filtrated over dicalite and the solvent was evaporated under reduced pressure to yield 1-(3,3- difluorocyclobutyl)-6-oxo-pyridine-3-carbaldehyde as an orange solid which was used for the subsequent reaction without further purification.
  • 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex 177 mg, 0.217 mmol
  • triethylamine 1.78 g, 2.45 ml, 17.85 mmol
  • the reactor was flushed 3 times with 7 bar of argon and five times with 10 bar of carbon monoxide.
  • the reactor was then filled with 8 bar of carbon monoxide, heated to 70 °C and stirred overnight for 18 h.
  • Step 2 5-(hydroxymethyl)-1-(trifluoromethyl)pyridin-2-one
  • methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate 750 mg, 3.39 mmol
  • toluene 22 ml
  • argon diisobutylaluminum hydride solution 1.2 M in toluene, 8.5 ml, 10.2 mmol
  • Step 3 6-oxo-1-(trifluoromethyl)pyridine-3-carbaldehyde
  • 5-(hydroxymethyl)-1-(trifluoromethyl)pyridin-2-one 520 mg, 2.69 mmol
  • dichloromethane (20 ml) manganese dioxide (2.34 g, 26.9 mmol) and the reaction mixture was stirred at room temperature for 96 h.
  • Step 4 [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate
  • 6-oxo-1-(trifluoromethyl)pyridine-3-carbaldehyde 175 mg, 0.458 mmol
  • dichloromethane 3 ml
  • 3-butyn-1-ol 48 mg, 52 ⁇ l, 0.688 ⁇ mol
  • reaction was cooled down to -10 °C and trifluoromethane sulfonic acid (206 mg, 121 ⁇ l, 1.37 mmol) was added dropwise via a syringe.
  • the mixture was stirred at - 10 °C for 60 min, then allowed to come to room temperature and stirred at ambient temperature for 3 h.
  • the reaction mixture was diluted with a saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness.
  • Step 5 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-1- (trifluoromethyl)pyridin-2-one
  • To a solution of [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (35 mg, 89 ⁇ mol) in 1,4-dioxane (1 ml) was added potassium acetate (35 mg, 0.356 mmol) and bis(pinacolato)diboron (29 mg, 0.116 mmol).
  • Step 2 ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino a]pyrimidin-7- yl]-3,6-dihydro-2H-pyran-2-carboxylate
  • 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidin-4-one (Intermediate B13, 2.33 g, 5.42 mmol) in 1,4- dioxane (108 ml) and water (18 ml) were added under argon stream ethyl 4- (trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (1.65 g, 5.42 mmol), potassium carbonate (2.25 g,
  • Step 4 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7- yl]tetrahydropyran-2-carboxylic acid
  • ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2- a]pyrimidin-7-yl]tetrahydropyran-2-carboxylate (246 mg, 0.535 mmol) in tetrahydrofuran (2 ml) and ethanol (1 ml) was added aqueous lithium hydroxide solution (1 M, 1.6 ml, 1.6 mmol) and the reaction mixture was stirred at room temperature.
  • Step 2 ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido b]pyridazin-7- yl]-3,6-dihydro-2H-pyran-2-carboxylate
  • 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin- 4-one (Intermediate B3, 2.1 g, 6.21 mmol) in 1,4-dioxane (50 ml) and water (5 ml) was added ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (2.45 g, 8.69 mmol), cesium carbonate (6.07 g, 18.63 mmol) and 1,1
  • Step 3 ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido b]pyridazin-7- yl]tetrahydropyran-2-carboxylate
  • platinum oxide 198 mg, 0.87 mmol, 0.2 eq
  • ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo- pyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate 2.0 g, 4.37 mmol
  • magnesium oxide (1.76 g, 43.7 mmol
  • triethylamine 530 mg
  • reaction was degassed with hydrogen three times, then stirred at 25 °C for 4 h under hydrogen (15 Psi).
  • the reaction mixture was filtered through a pad of diatomaceous earth, then poured into water (150 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (50 ml x 3) and dried over Na2SO4, then concentrated in vacuum.
  • Step 4 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylic acid
  • ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylate 1.3 g, 2.83 mmol
  • tetrahydrofuran (12 ml) and water (4 ml) was added lithium hydroxide monohydrate (178 mg, 4.24 mmol) and the reaction was stirred at 20 °C for 1 h.
  • Example 1 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one
  • the mixture was degassed with argon before tris(dibenzylideneacetone)dipalladium (9 mg, 0.0098 mmol, 0.05 eq) and Xantphos (11 mg, 0.0196 mmol, 0.10 eq) was added.
  • the reaction mixture was stirred overnight at 100 °C, then it was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness.
  • Example 2 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 1 from Intermediate (-)-C1 instead of Intermediate (+)-C1.
  • Example 3 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 1 from Intermediate B2 instead of Intermediate B1.
  • Example 4 and Example 5 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one
  • To a suspension of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin- 4-one (Intermediate B1, 50 mg, 0.13 mmol) in 1,4-dioxane (3 ml) was added 2-(2-methyl-4- pyridyl)morpholine (Intermediate C2, 28 mg, 0.16 m
  • reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml ⁇ 2). The combined original layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 ⁇ m, 100 ⁇ ; water with 0.1% formic acid / acetonitrile, flow rate 50 ml/min) to give 9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one (40 mg).
  • reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0-10%) to yield the title compound (19 mg, 14% yield) as light brown solid, MS m/z: 469.2 [M+H] + , ESI pos.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[1,2-a]pyrimidin-4-one
  • Example 16 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one Racemic 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[1,2-a]pyrimidin-4-one was separated by chiral SFC (column IB, 250 mm ⁇ 20 mm, 5 ⁇ m, 30% methanol) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrid
  • Example 17 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[1,2-b]pyridazin-4-one was separated by chiral SFC (column OD-H, 250 mm ⁇ 20 mm, 5 ⁇ m, 25% methanol + 0.2% diethylamine) to give 9-(4-chloro-2-fluorophenyl)-2,3- dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[1,2-b
  • Example 18 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 from Intermediate C9 instead of Intermediate C8. Light yellow powder, MS m/z: 467.3 [M+H] + , ESI pos.
  • Example 19 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridin-4-yl)morpholin- 4-yl]pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 14 from Intermediate C2 instead of Intermediate C1.
  • Example 20 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 1 from Intermediate B4 instead of Intermediate B1.
  • Example 21 and Example 22 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one
  • the title compounds was prepared in analogy to Example 15 from Intermediate B2 instead of Intermediate B1.
  • the racemate was separated by chiral SFC (column Chiral IJ, 250 mm ⁇ 20 mm, 5 ⁇ m, 20% methanol) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one as first eluting enantiomer with retention time 1.921 min, white powder, MS m/z: 493.4 [M+H] + , ESI pos.
  • Example 29 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B4 instead of Intermediate B1 and using Intermediate C9 instead of Intermediate C8.
  • the racemate was separated by chiral SFC (Chiralpak Cel-SZ, 250 mm ⁇ 20 mm, 5 ⁇ m, 53% methanol) to give 9- (4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[1,2-a]pyrimidin-4-one as first eluting enantiomer with retention time 2.809 min, white powder, MS m/z: 449.4 [M+H] + , ESI pos.
  • the absolute stereochemistry was assigned arbitrarily.
  • Example 30 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B2 instead of Intermediate B1 and using Intermediate C11 instead of Intermediate C8.
  • the compound is a racemic mixture.
  • the following Examples 31 to 33 were prepared in analogy to Examples 4 and 5 by starting from the indicated intermediates.
  • Example 32 is a racemate, the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates (ESI): m/z 9-(4-chloro-2-fluoro- phenyl)-2- (difluoromethyl)-3- methyl-7-[(2S)-2-(1- 504.2 31 B5 and (+)-C1 methylpyrazol-4- [M+H] + yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin- 4-one 9-(4-chloro-2-fluoro- phenyl)-7-[(2S,6S)-2-(1- cyclopropylpyrazol-4-yl)- 508.1 32 B1 and C7 6-methyl-morpholin-4-yl]- [M+H] + 2,3-dimethyl-pyrido[1,2- a]pyrimidin-4-one 9-(4-chloro-2,6- Cl difluorophenyl)-2,3- dimethyl
  • the formed racemate was separated by chiral SFC (column Chiral IB, 250 mm ⁇ 20 mm, 5 ⁇ m, 25% methanol) to give 9- (4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4- pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one as first eluting enantiomer with retention time 1.875 min, light yellow oil, MS m/z: 533.4 [M+H] + , ESI pos.
  • Example 36 and Example 37 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl- 1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4- yl]pyrazino[1,2-a]pyrimidin-4-one Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one was separated by chiral SFC (column Chiral AD-H, 250 mm ⁇ 20 mm, 5 ⁇
  • Example 38 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazol-4- yl)oxan-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B2 instead of Intermediate B1 and Intermediate C9 instead of Intermediate C8.
  • Example 39 and Example 40 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4- yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2- fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2- b]pyridazin-4-one formate
  • 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin- 4-one (Intermediate B3, 97 mg, 0.29 mmol) in dimethylsulfoxide (10 mL) was added diisopropyl ethylamine (0.15
  • reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml x 2) and dried over Na 2 SO 4 , then concentrated in vacuum.
  • Example 41 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazol- 4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B6 instead of Intermediate B1 and Intermediate C9 instead of Intermediate C8.
  • Example 42 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one
  • To a solution of 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrimido[1,2- b]pyridazin-4-one (Intermediate B7, 50 mg, 0.14 mmol) in acetonitrile (1.4 ml) were added (2S)- 2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-C1, 23.5 mg, 0.140 mmol) and a 3 M aqueous solution of tripotassium phosphate (3.25M, 0.140 mL, 0.421 mmol).
  • Example 48 9-(4-chloro-2-fluoro-phenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 1 using Intermediate B8 instead of Intermediate B1. Yellow solid, MS m/z: 454.4 [M+H] + , ESI pos.
  • the following Examples 49 to 56 were prepared in analogy to Examples 42 by starting from the indicated intermediates. Chiral separation was performed as described for Examples 4 and 5. The absolute stereochemistry was assigned arbitrarily. MS Ex.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one
  • dichloromethane 10 ml
  • trifluoroacetic acid 5.0 ml, 67 mmol
  • the reaction mixture was added water (40 ml) and aqueous sodium carbonate solution was added to the reaction to adjust pH to 7-8. It was extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by reversed phase chromatography (column: spherical C18, 20-45 mm 100 ⁇ , mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%, flow rate 80 ml/min) to afford the title compound (120 mg, 74% yield) as light yellow solid, MS m/z: 454.2 [M+H] + , ESI pos.
  • 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin- 4-one (Intermediate B2, 150 mg, 0.44 mmol) in 1,4-dioxane (5 ml) was added 2-(1- cyclopropylpyrazol-4-yl)morpholine
  • the title compounds were prepared in analogy to Example 66 and 67 using Intermediate C4 instead of Intermediate C5.
  • Example 75 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1- cyclopropylpyrazol-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B6 instead of Intermediate B1 and Intermediate C11 instead of Intermediate C8. Yellow solid, MS m/z: 512.3 [M+H] + , ESI pos.
  • Example 76 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 42 using Intermediate B11 instead of Intermediate B7.
  • the absolute stereochemistry was assigned arbitrarily.
  • Example 77 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazol- 4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one
  • the title compounds was prepared in analogy to Example 15 using Intermediate B3 instead of Intermediate B1 and Intermediate C11 instead of intermediate C8. Yellow solid, MS m/z: 494.3 [M+H] + , ESI pos.
  • Example 78 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxan-4-yl]- 2,3-dimethylpyrimido[1,2-b]pyridazin-4-one Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 77) was separated by chiral SFC (Column chiral OD-H, 5 ⁇ m, 250 x 20 mm, 33% methanol) to give the title compound as first eluting enantiomer with retention time 3.184 min, yellow solid, MS m/z: 494.1 [M+H] + , ESI pos
  • Example 84 and Example 85 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidin-4-one and 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compounds were prepared in analogy to Example 15 from Intermediate B12 instead of Intermediate B1 and intermediate C11 instead of C8.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • 7-[6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one 710 mg, 1.31 mmol) in 1,4-dioxane (12 ml) were added under argon 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M solution in tetrahydrofuran, 0.450 ml, 1.58 mmol), potassium carbonate (543 mg, 3.93 mmol) and
  • reaction mixture was filtered over Celite and washed with ethyl acetate.
  • the filtrate was poured into water and extracted with ethyl acetate twice.
  • the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo.
  • Step 3 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4- pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (482 mg, 1.01 mmol) was dissolved in methanol (25 ml).
  • the mixture was degassed with argon, then palladium on charcoal (10%, 108 mg) was added and the reaction mixture was stirred under hydrogen gas atmosphere (balloon) at room temperature for 2 h.
  • the reaction mixture was filtered over Dicalite, washed with ethyl acetate and the filtrate was concentrated in vacuo.
  • Example 93 and Example 94 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2- methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[1,2-a]pyrimidin-4-one Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)(2S,4R)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (Example 92) was separated
  • Example 95 and Example 96 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[1,2-a]pyrimidin-4-one Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazol-4- yl)oxan-4-yl]pyrazino[1,2-a]pyrimidin-4-one (Example 38) was
  • Example 97 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was isolated as minor diastereomer during the last step of the synthesis of Example 38, white solid, MS m/z: 468.2 [M+H] + , ESI pos.
  • Example 98 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4- yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B7 instead of Intermediate B1 and Intermediate C9 instead of Intermediate C8. Chiral separation was performed by chiral SFC (column Chiral IK, 250 mm ⁇ 20 mm, 5 ⁇ m, 37% methanol), second eluting enantiomer. Yellow solid, MS m/z: 486.2 [M+H] + , ESI pos.
  • the absolute stereochemistry was assigned arbitrarily.
  • the following Examples 99 to 109 were prepared in analogy to Examples 15 by starting from the indicated intermediates. Chiral separation was performed as described for Examples 95 and 96.
  • the absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex.
  • the reaction was degassed with nitrogen three times and the reaction mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin- 4-one 400 mg, 0.69 mmol) in ethyl acetate (40 ml), magnesium oxide (277 mg, 6.87 mmol) and triethylamine (0.11 ml
  • Step 3 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[(2S,4R)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one 700 mg, 0.72 mmol
  • reaction mixture was carefully poured into aqueous sodium bicarbonate solution (20 ml) and extracted with dichloromethane (50 ml x 3). The combined layers were washed by brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(5- cyclopropyl-1,3,4-oxadiazol-2
  • the title compounds were prepared in analogy to Example 66 and 67 using Intermediate C25 instead of Intermediate C5.
  • Step 2 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7- yl]tetrahydropyran-2-carbonitrile
  • 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin- 7-yl]tetrahydropyran-2-carboxamide 140 mg, 0.32 mmol
  • pyridine 0.08 ml, 0.97 mmol
  • trifluoroacetic anhydride (0.14 ml, 0.97 mmol
  • Step 3 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-N- hydroxy-tetrahydropyran-2-carboxamidine
  • hydroxylamine hydrochloride 50 mg, 0.73 mmol
  • triethylamine 98 mg, 0.97 mmol
  • 1,4-dioxane 1,4-dioxane
  • 4-[9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carbonitrile 100 mg, 0.24 mmol
  • reaction mixture was stirred at 20 °C for 16 h, then it was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and concentrated in vacuum.
  • Step 5 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-[(2S,4R)-2-(5-cyclopropyl- oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(5- oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-
  • Example 178 and Example 179 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl- 3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro- 2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrimido[1,2-b]pyridazin-4-one
  • the title compounds were prepared by chiral separation of 9-(4-chloro-2-fluorophenyl)-2,3- dimethyl-7-[rac-(2R,4S)-2-(6-keto-1-methyl- 3-pyridyl)tetrahydropyran-4-yl]-2
  • the absolute stereochemistry was assigned arbitrarily. Yellow solids, MS m/z: 495.2 [M+H] + , ESI pos.
  • the following Examples 180 to 190 were prepared in analogy to Example 15 by starting from the indicated intermediates. Reduction in step 2 was performed with addition of magnesium oxide and triethylamine as described for Examples 131 and 132. Chiral separation was performed as described for Examples 178 and 179.
  • the absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex.
  • reaction mixture was heated to 60 °C and stirred for 2.5 h, then it was filtered through dicalite and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one To a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(1-cyclopropyl-6-keto-3-pyridyl)-3,6- dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a
  • the mixture was purged and backfilled with argon three times, then it was heated to 60 °C and stirred for 1.5 h.
  • the reaction mixture was filtered through dicalite and washed with ethyl acetate twice.
  • the filtrate was poured into water and extracted with ethyl acetate.
  • the combined organic layers were dried (Na2SO4) and evaporated.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]pyrimido b]pyridazin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4- yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (720 mg, 1.45 mmol) in 1,4-dioxane (12 ml) were added under argon stream a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in tetrahydrofuran, 538 ⁇ l, 1.88 mmol), potassium carbonate (600 mg, 4.
  • reaction mixture was heated to 90 °C and stirred for 2 h. After cooling to room temperature, it was filtered over celite and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo.
  • Step 3 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrimido b]pyridazin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6- dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (380 mg, 0.757 mmol) in ethanol (15 ml) was added palladium on charcoal (10%, 84 mg) under argon and the mixture was stirred under hydrogen gas atmosphere (balloon pressure) at room temperature for 10 h.
  • Example 198 and Example 199 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2- methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrimido[1,2-b]pyridazin-4-one Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 197) was separated
  • Example 200 9-(2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one
  • This compound was formed as by-product at the hydrogenation step during the synthesis of Example 89 and 90 and was isolated by column chromatography (silica gel, 10% methanol in dichloromethane) after this reaction (18% yield), yellow solid, MS m/z: 461.4 [M+H] + , ESI pos.
  • Example 201 and Example 202 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H- pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4- chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one Step 1: 9-(4-chloro-2-fluoro-phenyl)-7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]- 2,3-dimethyl-pyrimido[1,2-b]pyridazin-4
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • triethylamine 78 mg, 107 ⁇ l, 0.767 mmol
  • magnesium oxide (257 mg, 6.39 mmol) in ethyl acetate (7 ml) was added platinum(IV) oxide (29 mg, 0.128 mmol, 0.20 eq) under argon and the
  • Step 3 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran- 4-yl]pyrimido[1,2-b]pyridazin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one 134 mg, 0.27 mmol
  • sodium iodide (40.5 mg, 0.27 mmol) in acetonitrile (5.5 ml) was added trimethylsilyl chloride (29 mg, 34 ⁇ l, 0.27 mmol) and the mixture was stirred at 65 °C for 3 h.
  • Step 4 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)- 2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3- yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one was separated by chiral
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2- fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-[1-(oxetan-3-ylmethyl)-6-oxo- 3-pyridyl]
  • step 2 Reduction in step 2 was performed with addition of magnesium oxide and triethylamine as described for Examples 131 and 132. Chiral separation was performed as described for Examples 178 and 179. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex.
  • Example 224 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 201 using Intermediate B16 instead of Intermediate B3 in step 1.
  • the absolute stereochemistry was assigned arbitrarily.
  • Example 225 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • Example 226 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-ethyl-6-keto-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 225 using 9-(4-chloro-2-fluoro-phenyl)- 7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2- b]pyridazin-4-one (Example 202) instead of 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto- 1H-pyridin-3-yl)tetrahydropyran-4-
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-[2-(cyclopropylmethoxy)-4- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 225 using 9-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-7-[rac-(2R,4S)-2-(2-oxo-1H-pyridin-4-yl)tetrahydropyran-4-yl]pyrimido[1,2- b]pyridazin-4-one instead of 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3- yl)tetrahydropyran-4-yl]-2
  • Example 247 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-[2-(cyclobutoxy)-4- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 246 using iodocyclobutane instead of iodomethylcyclopropane in step 2, yellow foam, MS m/z: 535.2 [M+H] + , ESI pos.
  • Example 248 7-[2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • Step 1 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2-oxo-1H-pyridin-4-yl)tetrahydropyran-4- yl]pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 202 using Intermediate B16 instead of Intermediate B3 and Intermediate C8 instead of Intermediate C35 in step 1, yellow solid, MS m/z: 471.3 [M+H] + , ESI pos.
  • Step 2 7-[2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-9- difluorocyclohexyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 225 using 9-(4,4-difluorocyclohexyl)- 2,3-dimethyl-7-[2-(2-oxo-1H-pyridin-4-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one instead of 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and io
  • Example 249 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-[2-(oxetan-3-ylmethoxy)-4- pyridyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 248 using 3-(bromomethyl)oxetane instead of iodomethylcyclopropane in step 2, white solid, MS m/z: 541.3 [M+H] + , ESI pos.
  • Example 250 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[(1R,5S)-6,6- difluoro-3-bicyclo[3.1.0]hexanyl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one
  • the title compound was prepared in analogy to Example 15 using Intermediate B21 instead of Intermediate B1 and Intermediate C11 instead of intermediate C8, white solid, MS m/z: 482.2 [M+H] + , ESI pos.
  • the absolute stereochemistry was assigned arbitrarily.
  • Example 251 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 191 using Intermediate B20 instead of Intermediate B13 and Intermediate C39 instead of Intermediate C29 in step 1, yellow solid, MS m/z: 513.2 [M+H] + , ESI pos.
  • the absolute stereochemistry was assigned arbitrarily.
  • Examples 252 to 254 were prepared in analogy to Examples 225 by alkylation of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4- yl]pyrimido[1,2-b]pyridazin-4-one (Example 201, step 3) using the indicated alkylating reagent.
  • the absolute stereochemistry was assigned arbitrarily.
  • step 2 Reduction in step 2 was performed with addition of magnesium oxide and triethylamine as described for Examples 131 and 132. Chiral separation was performed as described for Examples 178 and 179. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex.
  • reaction mixture was diluted with dichloromethane, absorbed on silica gel and purified by column chromatography (silica gel, 0-100% ethyl acetate / ethanol 3:1 with 2% ammoniumhydroxide in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H- pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (44 mg, 40% yield) as brown solid, MS m/z: 479.3 [M+H] + , ESI pos.
  • Step 2 9-(4-chloro-2-fluoro-phenyl)-7-[6-[1-(2,2-difluoroethyl)-6-oxo-3-pyridyl]-3,6-dihydro- 2H-pyran-4-yl]-2,3-dimethyl-pyrazino a]pyrimidin-4-one
  • Step 3 9-(4-chloro-2-fluoro-phenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one
  • 9-(4-chloro-2-fluoro-phenyl)-7-[6-[1-(2,2-difluoroethyl)-6-oxo-3-pyridyl]-3,6- dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one 29 mg, 53 ⁇ mol) in ethyl acetate (1.6 ml) were added magnesium oxide (21 mg, 534 ⁇ mol) and triethylamine (6.5 mg, 9 ⁇ l, 65 ⁇ mol).
  • the flask was purged with argon, then palladium on charcoal (10%, 11 mg) was added and the flask was purged with argon again. After filling with hydrogen, the reaction was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 8 h. The reaction mixture was filtered through Dicalite and concentrated under reduced pressure.
  • step 2 Reduction in step 2 was performed with addition of magnesium oxide and triethylamine as described for Examples 131 and 132. Chiral separation was performed as described for Examples 178 and 179. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex.
  • Example 284 and Example 285 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl- 6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4- chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one Step 1: 9-(4-chloro-2,6-difluoro-phenyl)-2,
  • Step 2 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2,6- difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one A mixture of 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[2-(6-o
  • Example 286 and Example 287 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran- 4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 7-[(2S,4R)-2- (1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one
  • the title compounds were prepared in analogy to Example 284 and 285 using Intermediate B15 instead of Intermediate B7.
  • Example 288 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg
  • Example 289 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

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Abstract

L'invention concerne des composés de formule générale (I) dans laquelle A1, A2, X1, X2, R1, R2, R3, R4 et R7 sont tels que décrits dans la description, des compositions comprenant les composés, des procédés de fabrication des composés et des procédés d'utilisation des composés dans le traitement ou la prévention de maladies qui sont associées à TREM2.
PCT/EP2024/066833 2023-06-19 2024-06-17 Agonistes de trem2 Pending WO2024260929A1 (fr)

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US12459953B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators
US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

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